The natural product, mitomycin C, has proven to be a clinically useful antitumor agent (Carter and Crooke, 1979, Mitomycin C Current Status and New Developments, Academic Press: New York). Mitomycin C is not active in the quinone form and requires activation by either enzymatic or chemical reduction (Tomasz et al., 1987, Science 235:1204-8; Cera et al., 1989, Biochemistry 28:5665-69). Mild acidic treatment also results in alkylated mitosene derivatives (Tomasz and Lipman, 1979, J. Am. Chem. Soc. 101:6063-67). The activated mitomycin C undergoes loss of methanol and is capable of monofunctional and/or bifunctional covalent interaction with DNA (Tomasz et al, 1987, supra).
The discovery of mitomycin C has resulted in two total syntheses of this important natural product (Fukuyama et al., 1977, Tetrahedron Lett. pp. 4295-98; Nakatsubo et al., 1977, J. Am. Chem. Soc. 99:8115-16; Nakatsubo et al., 1977, J. Am. Chem. Soc. 99:4835-36; Kishi, 1979, J. Nat. Prod. 42:549-568) (Fukuyama et al., 1987, J. Am. Chem. Soc. 109:7881-82; Fukuyama and Yang, 1989, J. Am. Chem. Soc. 111:8303-4; Fukuyama and Yang, in Studies in Natural Products Chemistry, Atta-ur-Rahman (ed.), 1973, Elsevier Science Publishers B.V. 13:433-471). However, one of these methods for the total synthesis of mitomycin C requires 46 steps, with an overall yield of 0.2%. The second method requires 31 steps, with an overall yield of 6%.
Two new natural products related to mitomycin, FR900482 and FR66979, have recently been isolated from a Streptomyces sandaensis culture (Uchida et al., 1987, J. Am. Chem. Soc. 109:4108-9; Iwami et at., 1987, J. Antibiot. 40:589-593; Kiyoto et al., ibid, 594-599; Shimomura et at, ibid., 600-606; Hirai et at., ibid., 607-611; Terano et al., 1989, J. Antibiot. 42:145-148). These compounds (Woo et al, 1993, J. Am. Chem. Soc. 115:1199-1200) appear to be activated by either enzymatic or chemical reduction, and thus alkylate DNA in a manner like mitomycin C (Tomasz et al, 1987, supra; Tomasz and Lipman, 1979, supra; Basu et at., 1993, Biochemistry 32:4708-18),.
Mitomycin C causes severe delayed myelosuppression (i.e., it lowers the whim blood cell count), which has limited its clinical usefulness. Mitomycin C has the lowest redox potential of the naturally occurring mitomycins. As indicated above, reduction of the quinone form of mitomycin is necessary to the antibiotic properties of this drug. It is believed that an analog having a lower redox potential would exhibit greater alkylating efficiency, and thus be more therapeutically attractive. However, the synthesis and testing of such structural has been hindered by the lengthy, cumbersome and impractical synthetic strategies presently available.
For example, the novel structure and potential usefulness of FR900482 makes it an attractive synthetic target. However, as with mitomycin, there is no practical method to synthesize this drug: a 40-plus step total syntheses (Fukuyama et at., 1992, J. Am. Chem. Soc. 114:383-385), and several partial syntheses (Yasuda and Williams, 1989, Tetrahedron Lett. 30:3397-3400; Fukuyama and Goto, 1989, Tetrahedron Lett. 30:6491-94; Jones and Rapoport, 1990, J. Org. Chem. 55:1144-46; McClure and Danishefsky, 1991, J. Org. Chem. 56:850-53; McClure et at., 1991, J. Am. Chem. Soc. 113:8185-86; Dmitrienko et at., 1992, Tetrahedron Lett. 33:5705-8; McClure and Danishefsky, 1993, J. Am. Chem. Soc. 115:6094- 6100) of FR900482 have been reported.
Thus, them is a need in the art for a facile, efficient and economical method for the synthesis of tetracyclic mitomycin, including analogs and intermediates thereof.
There is a further need in the art for a facile, efficient and economical method for the synthesis of tetracyclic natural product analogs of mitomycin, including analogs and intermediates thereof.
There is yet a further need in the art to identify mitomycin analogs that demonstrate improved anticancer activity, decreased toxicity, or both.
These and other needs in the art are addressed by the present invention.
The citation of any reference herein is not an admission that such reference is available as prior art to the present invention.